2. Academic Validation
  3. 18β-glycyrrhetyl-3-O-sulfate would be a causative agent of licorice-induced pseudoaldosteronism

18β-glycyrrhetyl-3-O-sulfate would be a causative agent of licorice-induced pseudoaldosteronism

  • Sci Rep. 2019 Feb 7;9(1):1587. doi: 10.1038/s41598-018-38182-2.
Kan'ichiro Ishiuchi 1,  Osamu Morinaga 2,  Takeshi Ohkita 1,  Chuanting Tian 1,  Asuka Hirasawa 1,  Miaki Mitamura 1,  Yasuhito Maki 1,  Tsubasa Kondo 2,  Tomoya Yasujima 3,  Hiroaki Yuasa 3,  Kiyoshi Minamizawa 4,  Takao Namiki 5,  Toshiaki Makino 6
Affiliations

Affiliations

  • 1 Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-Dori, Mizuho-ku, Nagoya, Japan.
  • 2 Department of Natural Medicines, Daiichi University of Pharmacy, 22-1 Tamagawamachi, Minami-ku, Fukuoka, Japan.
  • 3 Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-Dori, Mizuho-ku, Nagoya, Japan.
  • 4 Department of Oriental Medicine, Kameda Medical Center, 929 Higashi-cho, Kamogawa, Japan.
  • 5 Department of Japanese-Oriental (Kampo) Medicine, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, Japan.
  • 6 Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-Dori, Mizuho-ku, Nagoya, Japan. makino@phar.nagoya-cu.ac.jp.
PMID: 30733510 DOI: 10.1038/s41598-018-38182-2
Abstract

Licorice-induced pseudoaldosteronism is a common adverse effect in traditional Japanese Kampo medicine, and 3-monoglucuronyl glycyrrhetinic acid (3MGA) was considered as a causative agent of it. Previously, we found 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide (1), one of the metabolites of glycyrrhizin (GL) in the urine of Eisai hyperbilirubinuria rats (EHBRs) treated with glycyrrhetinic acid (GA), and suggested that it is also a possible causative agent of pseudoaldosteronism. The discovery of 1 also suggested that there might be other metabolites of GA as causal candidates. In this study, we found 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate (2) and 18β-glycyrrhetyl-3-O-sulfate (3) in EHBRs' urine. 2 and 3 more strongly inhibited rat type 2 11β-hydroxysteroid dehydrogenase than 1 did in vitro. When EHBRs were orally treated with GA, GA and 1-3 in plasma and 1-3 in urine were detected; the levels of 3MGA were quite low. 2 and 3 were shown to be the substrates of organic anion transporter (OAT) 1 and OAT3. In the plasma of a patient suffering from pseudoaldosteronism with rhabdomyolysis due to licorice, we found 8.6 µM of 3, 1.3 µM of GA, and 87 nM of 2, but 1, GL, and 3MGA were not detected. These findings suggest that 18β-glycyrrhetyl-3-O-sulfate (3) is an alternative causative agent of pseudoaldosteronism, rather than 3MGA and 1.

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